Malaria is an acute and often chronic infectious disease resulting from the presence of protozoan parasites within red blood cells. Caused by single-celled parasites of the genus Plasmodium, malaria is transmitted from person to person by the bite of female mosquitoes.
The discovery of artemisinin (qinghaosu), a naturally occurring endoperoxide sesquiterpene lactone (Meshnick et al., Microbiol. Rev. 60, 301-315, 1996; Vroman et al., Curr. Pharm. Design 5,101-183, 1999; Dhingra et al., Life Sci. 66, 279-300, 2000) initiated a substantial effort to elucidate its molecular mechanism of action (Jefford, Adv. Drugs Res. 29, 271-325, 1997; Cumming et al., Adv. Pharmacol. 37, 254-297, 1997) and to identify novel antimalarial peroxides (Dong and Vennerstrom, Expert Opin. Ther. Patents 11, 1753-1760, 2001). Many synthetic 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and other endoperoxides have been prepared.
Although the clinically useful semisynthetic artemisinin derivatives are rapid acting and potent antimalarial drugs, they have several disadvantages including recrudescence, neurotoxicity, (Wesche et al., Antimicrob. Agents. Chemother. 38, 1813-1819, 1994) and metabolic instability. (White, Trans. R. Soc. Trop. Med. Hyg. 88, 41-43, 1994). A fair number of these compounds are quite active in vitro, but most suffer from low oral activity. (White, Trans. R. Soc. Trop. Med. Hyg. 88, 41-43, 1994; van Agtmael et al., Trends Pharmacol. Sci. 20, 199-205, 1999). Although many synthetic antimalarial 1,2,4-trioxanes have since been prepared (Jefford, Adv. Drugs Res. 29, 271-325, 1997; Cumming et al., Adv. Pharmacol. 37, 254-297, 1997), there exists a need to identify new antimalarial agents, especially those which are easily synthesized, are devoid of neurotoxicity.
A synthetic procedure for preparing compounds of Formula I, salts of the free base cis-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methyl propyl)amino]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane has been disclosed in U.S. Pat. No. 6,906,205.